Carboxypeptidases are proteases that function in many physiological processes. These proteases remove a wide range of carboxyl-terminal amino acids, and in doing so are able to activate, inactivate, and modulate enzyme and peptide hormone activity. Many active forms of mammalian carboxypeptidases are located in lysosomes where they regulate intracellular protein processing, degradation and turnover. In plants and insects carboxypeptidases play a role in posttranslational protein modifications including mobilization of storage proteins and hormone activation.
Carboxypeptidase activities are regulated either by endogenous protein inhibitors or by enzymatic cleavage of a segment of a propeptide to release the active carboxypeptidase. Carboxypeptidases A and B (CPA and CPB, respectively) are pancreatic zinc-containing proteolytic enzymes which catalyze the hydrolysis of the carboxyl-terminal peptide bond in polypeptide chains. When transcribed in rat brain and other nonpancreatic tissues, CPA is unable to function as a protease (Normant, E. et al. (1995) J. Biol. Chem. 270: 20543-20549). This inability to function as a protease has been attributed to the presence of tissue-specific, endogenous protein inhibitors such as tissue carboxypeptidase inhibitor (TCI) or latexin (Normant, E. et al. (1995) Proc. Natl. Acad. Sci. 92: 12225-12229; Hatanaka, Y. et al. (1994) Eur. J. Neurosci. 6: 973-982).
Latexin and TCI are 222 and 223 amino acids in length, respectively. They contain several potential phosphorylation sites, but they do not show a membrane-specific signal peptide sequence (Normant et al., supra; Hatanaka et al., supra). TCI is a non-competitive, nearly irreversible, and potent inhibitor of CPA; it is less potent against CPB and does not act on various other proteases. TCI and latexin are both expressed and localized in the cytosol of a number of tissues including brain, lung, or digestive tract. It has been suggested that TCI or latexin may function in regulating tissue-specific, cytosolic protein degradation (Normant et al., supra).
The discovery of a new human carboxypeptidase inhibitor and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of inflammation and disorders associated with cell proliferation and apoptosis.